Optineurin is an autophagy receptor for damaged mitochondria in parkin-mediated mitophagy that is disrupted by an ALS-linked mutation
Open accessAbstract
Significance: In mitophagy, damaged mitochondria recruit parkin to ubiquitinate proteins on the outer mitochondrial membrane, targeting mitochondria for autophagosome engulfment and degradation. However, the proteins involved in mediating autophagosome formation to degrade damaged and ubiquitinated mitochondria remain unknown. We used live cell imaging to demonstrate that optineurin is actively recruited to parkin-labeled ubiquitinated mitochondria and is stabilized by its ubiquitin binding domain. Optineurin binds the autophagosome protein LC3 (microtubule-associated protein light chain 3), and this binding recruits autophagosome assembly around damaged mitochondria. We find that the E478G optineurin mutation, causative for the neurodegenerative disease amyotrophic lateral sclerosis, disrupts autophagosome recruitment. As mutations in parkin are linked to Parkinson’s disease, this study indicates that defects in a single mitochondrial degradation pathway lead to neurodegenerative diseases with distinct pathologies.
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Upon mitochondrial damage, OPTN translocates to the surface of mitochondria, an interaction stabilized via TBK1-mediated phosphorylation, facilitating engulfment of mitochondria into phagophores.
“Upon mitochondrial damage, OPTN translocates to the surface of mitochondria, an interaction that is stabilized via TBK1-mediated phosphorylation, facilitating the engulfment of mitochondria into phagophores [256].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [256]
Mitophagy can also occur through Parkin-independent pathways.
“Mitophagy can also occur through Parkin-independent pathways.”
From Mitochondrial Dynamics and Mitophagy in Skeletal Muscle Health and Aging (2021) · cites this paper as [141]
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“A constitutive pathway for axonal autophagy has been reported in neurons both in vitro (Maday and Holzbaur, 2014; Wong and Holzbaur, 2014b) and in vivo (Neisch et al., 2017; Soukup et al., 2016; Stavoe et al., 2016).”
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- Authors
- Wong, Y. C., & Holzbaur, E. L. F.
- Affiliations
- University of Pennsylvania (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2014-10-07
- Volume
- 111
- Issue
- 42
- Pages
- E4439-48
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4210283
- OpenAlex
- W2051362437
- Cited by
- 812
- References
- 47
- Citations by year
- 2026: 34 · 2025: 62 · 2024: 58 · 2023: 68 · 2022: 68 · 2021: 94 · 2020: 88 · 2019: 80 · 2018: 64 · 2017: 61 · 2016: 71 · 2015: 60 · 2014: 4
- FWCI
- 49.50
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (R37NS060698, R01NS060698)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- optineurin, mitophagy, Parkin, autophagy receptors, amyotrophic lateral sclerosis, E3 ubiquitin ligase, LC3, autophagosome formation, p62, mitochondrial dysfunction, ubiquitin-binding domain, reactive oxygen species, mitochondrial depolarization, neurodegenerative diseases
- MeSH terms
- Sequestosome-1 Protein, Amyotrophic Lateral Sclerosis, Autophagy, HeLa Cells, Humans, Microtubule-Associated Proteins, Microtubules, Mitochondria, Mutation, Parkinson Disease, Phagosomes, Protein Binding, Protein Structure, Tertiary, Microscopy, Confocal, Cell Cycle Proteins, Neurodegenerative Diseases, Membrane Transport Proteins, RNA, Small Interfering, Transcription Factor TFIIIA, Ubiquitin-Protein Ligases, Adaptor Proteins, Signal Transducing, Green Fluorescent Proteins, Mitochondrial Membranes, Mitophagy
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